Among lifestyle-related diseases, in particular, diabetes is considered to be one of the most serious social problems because many patients are suffering from diabetes. There are plural causes to bring this diabetes state, but the direct cause of an increase in blood sugar level greatly depends on a decrease in insulin secretion or a decrease in insulin action.
β-cells, which are distributed in the Langerhans islets of the pancreas, are responsible for insulin secretion. The β-cells secrete and release insulin into the blood when glucose stimulus is applied on the cells. Insulin acts on muscle cells, fat cells, liver cells, and so on to allow glucose in blood to be imported into these cells to keep the blood sugar level constant. When the blood sugar level is kept high owing to the diabetes state, specific complications will be developed in the retina, kidney, nerve, artery, and so on.
To date, therapeutic agents for diabetes mainly focused on two functional sites (for accelerating the insulin secretion and accelerating the insulin action) have been developed and some of them have resulted in considerable effects. However, those therapeutic methods are not more than symptomatic treatments, so that they cannot attain radical therapies even though they may improve a disease state or retard the progress of the disease state. For instance, an insulin-secretion accelerator triggers a transient increase in insulin secretion. However, it has been pointed out as a real problem that the continuous usage of the drug for a long time would exhaust β-cells to irreversibly attenuate their insulin-secreting abilities. Therefore, returning the insulin-secreting functions of β-cells (which decrease as the state of diabetes progresses) to normal is nothing but restoring the β-cells themselves to normal.
Furthermore, there are various kinds of peptide hormones in the living body, which are responsible for the glucose metabolism as in the case of insulin. Among them, glucagon-related peptides to be produced from the pancreas and digestive tract are important from the viewpoint of insulin-like blood sugar regulation. The glucagon-related peptides are synthesized at first as precursors thereof, or preproglucagon. Then, the preproglucagon is processed differently depending on the respective organs. For example, the pancreas mainly produces glucagon and the digestive tract mainly produces both glucagon-like peptide (GLP)-1 and GLP-2. Possible main physiological functions of those peptide hormones are as follows. That is, glucagon accelerates the gluconeogenesis with glycogenolysis in the liver, GLP-1 accelerates the insulin secretion (the incretin action thereof) from the pancreas, and GLP-2 regulates the functions of digestive tract (e.g., see Ann N Y Acad Sci 1988; 527: 168-85).
Among them, GLP-1 was initially identified as a 37-amino acid peptide having the amino acid sequence from position 92 to position 128 of a preproglucagon peptide (hereinafter, the peptide may be referred to as GLP-1(1-37)) (e.g., see Peptides 1981; 2 Suppl 2: 41-4). After that, it was revealed that a 31-amino acid peptide (GLP-1(7-37)) starting from histidine, the amino acid at position 7, and an amide thereof constitute the substantial material of the in vivo activation and act as incretin (e.g., see J Clin Invest 1987 February; 79 (2): 616-9 and N Engl J Med 1992 May 14; 326 (20): 1316-22). GLP-1(7-37) or a receptor agonist thereof has been expected to be an antidiabetic drug, where the acceleration of insulin-secretion from pancreatic β-cells is provided as the functional site.
GLP-1(1-37) shows a weak activity as incretin. Thus, GLP-1(7-37) has been provided not only as an antidiabetic drug but also as a main subject in the study of incretin. In other words, under the present circumstances, GLP-1(7-37) is considered to be the original of GLP-1, while GLP-1(1-37) is simply considered to be an intermediate which is generated from the precursor peptide in the processing process (e.g., see J Clin Invest 1987 February; 79 (2): 616-9).
Recently, the action of GLP-1(7-37) has been found to act on precursor cells for β-cells to induce the differentiation therefrom so as to be differentiated as insulin-positive cells. Therefore, regenerative medical procedures, which target on the restoration of β-cells, i.e., the recovery of the pancreatic functions, have been remarked in the art (e.g., see Endocrinology 2002 August; 143 (8): 3152-61).
Mainly two approaches have been investigated. One is a method for transplanting β-cells after growing and differentiating the cells in vitro, and the other is a method of inducing the differentiation of β-cells directly from their precursor cells or inducing the differentiation of insulin-producing cells. For establishing a therapeutic method, it is indispensable to widely use the method for inducing the differentiation of β-cells.